Genomes and Genes
Brain tumors with regulatory T-cells treated with EGFRvIII-specific T-cells
Principal Investigator: John H Sampson
Abstract: DESCRIPTION (provided by applicant): Malignant primary brain tumors represent the most frequent cause of cancer death in children and young adults and account for more deaths than cancer of the kidney or melanoma. Glioblastoma (GBM) is uniformly lethal, and current therapy is non-specific and produces a median overall survival of <15 months. In contrast, immunotherapy promises an exquisitely precise approach, and substantial evidence suggests that T-cells can eradicate large, well-established tumors in mice and humans even when tumors reside within the brain. Chimeric antigen T-cell receptors (CARs) combine the variable region of an antibody with T-cell signaling moieties to confer T-cell activation with the targeting specificiy of an antibody and are not MHC-restricted. Additionally, co-stimulatory molecules, such as CD28 and 4-1BB, can be added to these constructs to improve T-cell expansion, survival, cytokine secretion, and tumor lysis. Clinical trials utilizing CARs have demonstrated their remarkable potential. However, severe adverse events and even patient deaths have occurred when these CARs have been directed against antigens shared by normal tissues. EGFRvIII is a tumor-specific mutation of the epidermal growth factor receptor that is expressed in GBMs and several other neoplasms. We have previously shown that EGFRvIII can be recognized by highly avid antibodies, so have developed human and murine CAR vectors that specifically recognize EGFRvIII inducing cytokine secretion and in vitro and in vivo tumor lysis. We have also demonstrated that an EGFRvIII-specific peptide (PEPvIII) contains the conformational epitope for EGFRvIII-specific antibodies used in these CARs. Using this peptide, we have shown that these cognate peptides are sufficient antidotes for CARs, suggesting a novel paradigm for reducing the target-specific toxicity of less tumor-specific CARs. Despite their potency, however, CARs still require host conditioning with lymphodepletion for efficacy and are still limited by being susceptible to inhibition by host immunosuppressive factors of which regulatory T-cells (TRegs) have been most frequently implicated. Similarly, while total body irradiation or non-therapeutic chemotherapy has been applied to optimize CAR therapy, it adds additional toxicity without direct anti-tumor efficacy. Our prior experience with TMZ demonstrates that, in addition to having direct clinical benefit in GBM, TMZ can potentiate anti-tumor immune responses directly related to the rebound homeostatic proliferation it induces. To address these issues, in this proposal, we will 1) Evaluate the risk of toxicity, utility of TMZ, and the requirements for efficacy of a tumor-specific, EGFRvIII-targeted CAR in a syngeneic, immunocompetent, orthotopic murine GBM model;2) Determine if CD3-CD28-4-1BB CAR vectors naturally transfect and activate TRegs and dissect the role of CAR-secreted IL-2 in supporting the growth of intratumoral TRegs and effector T-cells;and 3) Conduct a Phase I clinical trial in TMZ-treated patients with EGFRvIII-expressing GBM to assess CAR safety, kinetics and function.
Funding Period: 2013-04-05 - 2018-03-31
more information: NIH RePORT
- Intracerebral delivery of a third generation EGFRvIII-specific chimeric antigen receptor is efficacious against human gliomaBryan D Choi
Duke Brain Tumor Immunotherapy Program, Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Box 3050, Durham, NC 27710, USA Department of Pathology, Duke University Medical Center, Durham, NC, USA
J Clin Neurosci 21:189-90. 2014..Importantly, these results endorse clinical translation of this CAR in patients with EGFRvIII-expressing brain tumors. ..
- EGFRvIII mCAR-modified T-cell therapy cures mice with established intracerebral glioma and generates host immunity against tumor-antigen lossJohn H Sampson
Authors Affiliations Duke Brain Tumor Immunotherapy Program, Division of Neurosurgery, Department of Surgery Department of Pathology The Preston Robert Tisch Brain Tumor Center at Duke, Duke University Medical Center Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina and Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
Clin Cancer Res 20:972-84. 2014..A constitutively activated mutant of the naturally occurring epidermal growth factor receptor (EGFRvIII) is antigenically identical in both human and mouse glioma, but is also completely absent from any normal tissues...
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